The present invention relates to novel dinitroglycerol ester derivatives of unsaturated fatty acids, hydroxy unsaturated fatty acids, and eicosanoids, and to methods of making and using them. It provides dinitroglycerol esters of a wide variety of compounds such as polyunsaturated fatty acids, prostaglandins and hydroxy fatty acids, having useful and improved properties relative to the parent compounds. These improved properties include, but are not limited to: greater functional specificity, an enhanced ability to stimulate uterine contraction, an enhanced ability to modulate bronchial and arterial contractions, an enhanced ability to prevent platelet aggregation, and fewer side effects. The esters provided herein are more membrane-soluble than their precursor compounds, and can therefore more readily penetrate through membrane barriers.
Fatty acids and their oxygenated derivatives ("oxilipins") play an important role in the biochemical regulatory processes of a wide range of organisms, including humans. For example, fatty acids are essential structural and functional components of biological membranes. They are also key precursors of important bio-active metabolites such as prostaglandins, leukotrienes, hydroxy-polyenoic acids, etc. Many fatty acids have been shown to themselves possess important bio-regulatory properties (e.g., the ability to effect structural and functional changes in membranes and to alter the metabolism of target cells). Some derivatives of fatty acids possess a wide spectrum of biological activities. For example, it has been reported that anandamide (arachidonoylethanolamide) is a ligand for cannabinoid receptors (W. A. Devane et al., Science. Vol. 258, pp. 1946-1949, 1992), and arachidonoylamide was found to inhibit leukotriene biosynthesis (E. J. Corey et al. J. Am.. Chem. Soc., 1984, Vol. 106, p. 1503).
The term "oxilipin" denotes oxygenated compounds which are formed from polyunsaturated fatty acids by a reaction or reactions wherein at least one step is an enzymatically catalyzed oxygenation. Oxilipins include leukotrienes, eicosanoids such as prostaglandins and hydroxy- and epoxy- fatty acids with a chain length of 20 carbon atoms, as well as biosynthetically related compounds of longer (e.g., C22) and shorter (e.g., C18) chain length.
Prostaglandins ("PGs") are eicosanoid oxilipins synthesized by a wide variety of human tissues. They share in common a prostanoic acid skeleton described by the following formula: ##STR1##
PGs are classified into several types according to the substituent groups present on their five-membered ring: ##STR2##
They are also classified according to the placement of their double bonds ##STR3##
Prostaglandins have been shown to possess a wide spectrum of properties and to play an important role in a broad range of biological processes. These include, but are not limited to: hypertension, vasodilation, induction of inflammation and other immune responses, platelet aggregation, mediation of uterine and enteric muscle contraction, and ocular hypotension.
Despite their well-recognized potential for clinical utility in treating a variety of medical conditions, the medical uses of PGs and other fatty acid derived drugs have often been significantly limited by their metabolic and chemical instability and by the existence of undesirable side effects. There is therefore a great need to generate and test chemical derivatives of PGs having properties that are similar to or an improvement over those of the parent compound, while at the same time having fewer or less severe side effects.
A number of synthetic PG drugs have been produced and are presently at different stages of clinical study or already in medical use. See, e.g., Raduchel, B. and Vorbruggen, H., Prostaglandin Analogs, Advances in Prostaglandin, Thromboxane, and Leukotriene Research, Vol. 14, pp. 263-307 (1985) edited by J. Pike and D. R. Morton, Jr., Raven Press, N.Y. It is possible to generally divide these PG drags into two groups. The first group consists of PG analogs in which the natural structures have been radically altered. (e.g., ILOPROST--a stable PGI.sub.2 analog, or ENPROSTIL--a PGE.sub.2 analog in which sites of enzymic attack are protected chemically). These substances have relatively long half-lives. The other group includes natural PGs or PGs with localized ("dot") modifications (e.g., fluoroprostaglandins). In these instances the increase in the modified prostanoid's half-life is usually achieved by creating a drug form that enables the controlled release of prostaglandins.
Many pathologies of the cardiovascular system are related to, or accompanied by, an increased platelet aggregation. Well known examples are myocardial infarction, ischemic brain damage, thrombosis, shock, etc. The presently existing platelet anti-aggregation drugs have a comparatively low specific activity and anti-aggregation activity is only one of numerous side effects. There is a need for drags combining a high anti-aggregation and vasodilating activities. Some of the novel fatty acid and prostaglandin derivatives described below have the potential to fill this gap.